本文關(guān)鍵詞：全基因組乳腺癌DNA甲基化與基因表達(dá)關(guān)聯(lián)模式　出處：《西安電子科技大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 乳腺癌 甲基化 基因表達(dá) 關(guān)聯(lián)模式

【摘要】：乳腺癌是一種嚴(yán)重威脅女性健康的惡性腫瘤,其發(fā)病率逐年上升并且具有發(fā)病者年輕化的趨勢(shì),但是其發(fā)病機(jī)制卻并不清晰,因此對(duì)于乳腺癌的研究非常必要。近年來的研究發(fā)現(xiàn)乳腺癌的發(fā)生是一個(gè)多因素綜合作用累積的結(jié)果,作為一種重要的表觀遺傳機(jī)制,DNA異常甲基化在乳腺癌中非常常見,且往往導(dǎo)致乳腺癌關(guān)鍵基因的表達(dá)異常,對(duì)乳腺癌的發(fā)生發(fā)展具有關(guān)鍵性的調(diào)節(jié)作用。目前在乳腺癌的DNA異常甲基化的研究方面,大部分都是針對(duì)單個(gè)基因或基因不同區(qū)域的DNA甲基化模式的研究,對(duì)DNA甲基化與基因表達(dá)之間關(guān)系的研究并不多,也不夠深入和詳細(xì),更沒有從全基因組的角度來對(duì)DNA甲基化與基因表達(dá)之間的關(guān)系進(jìn)行全面系統(tǒng)的分析。因此,針對(duì)目前研究上存在的不足,本文在全基因組的層面上對(duì)乳腺癌DNA甲基化與基因表達(dá)之間的關(guān)聯(lián)模式進(jìn)行了探討,主要取得的創(chuàng)新性成果如下:1.針對(duì)全基因組上DNA甲基化與基因表達(dá)數(shù)據(jù)的高維性和關(guān)系的復(fù)雜性,本文提出了一種基于差異化分析和聚類的DNA甲基化與基因表達(dá)關(guān)系分析方法。該方法首先應(yīng)用SAM差異分析方法篩選出差異表達(dá)基因和差異甲基化的CpG位點(diǎn);然后利用AP聚類算法先對(duì)差異甲基化的CpG位點(diǎn)根據(jù)相似性聚類形成多個(gè)甲基化簇,再針對(duì)每個(gè)甲基化簇對(duì)應(yīng)的基因表達(dá)數(shù)據(jù)利用AP聚類形成多個(gè)基因表達(dá)簇,即得到多個(gè)甲基化簇和多組基因表達(dá)簇;最后對(duì)相應(yīng)簇的甲基化數(shù)據(jù)和基因表達(dá)數(shù)據(jù)進(jìn)行組合即得到兩者之間的多種關(guān)聯(lián)模式。在上述聚類過程中,該方法通過迭代和設(shè)置閾值的方式來避免得到過多的聚類,通過取聚類簇的均值作為簇代表模式的方式來降低計(jì)算復(fù)雜性。同時(shí)該方法可以根據(jù)需要調(diào)整差異分析方法和聚類方法,具有良好的擴(kuò)展性。2.本研究對(duì)全基因組上乳腺癌DNA甲基化與基因表達(dá)的關(guān)聯(lián)模式進(jìn)行分析發(fā)現(xiàn),得到的關(guān)聯(lián)模式具有顯著特點(diǎn)。首先,各類別中的患病樣本與正常樣本之間存在明顯差異性,可基本區(qū)分開。其次根據(jù)患病樣本與正常樣本的差異性區(qū)別得到的八個(gè)類別中,DNA甲基化與基因表達(dá)的關(guān)聯(lián)模式具有類間顯著不同,類內(nèi)大致相似的趨勢(shì)。最后,每個(gè)大類中,DNA甲基化與基因表達(dá)之間的關(guān)聯(lián)模式存在著微小的差異,類內(nèi)各關(guān)聯(lián)模式的主要區(qū)別在于其甲基化水平和基因表達(dá)水平值的分布范圍。3.實(shí)驗(yàn)分析證明了所得到的關(guān)聯(lián)模式具有良好的生物解釋性。首先,各關(guān)聯(lián)模式都存在已知乳腺癌關(guān)鍵致病基因的支持,為新的乳腺癌關(guān)鍵基因的發(fā)現(xiàn)及其關(guān)聯(lián)模式的研究提供了依據(jù);其次,對(duì)各類別的基因集進(jìn)行生物通路富集性分析發(fā)現(xiàn),各基因集在多個(gè)乳腺癌關(guān)鍵通路中存在顯著富集,對(duì)乳腺癌的發(fā)生發(fā)展起著重要調(diào)控作用。綜上,本研究從全基因組的層面上對(duì)乳腺癌DNA甲基化與基因表達(dá)之間的關(guān)系進(jìn)行了詳細(xì)研究和分析,初步建立了乳腺癌DNA甲基化與基因表達(dá)之間的關(guān)聯(lián)模式,也為乳腺癌的預(yù)后、診斷和治療提供了方法和依據(jù)。
[Abstract]:Breast cancer is a serious threat to the health of women malignant tumor, its incidence has increased year by year and the incidence trend of younger, but its pathogenesis is not clear, so the research of breast cancer is very necessary. The study found that in recent years the occurrence of breast cancer is the accumulation of several factors results. As an important epigenetic mechanism, DNA methylation is common in breast cancer, and often leads to abnormal expression of key genes of breast cancer, regulation is the key to the development of breast cancer. At present, in the study of breast cancer DNA methylation, most of them are on a single gene or gene DNA methylation patterns in different regions, not much research on DNA methylation and gene expression of the relationship between the lack of in-depth and detailed, but not from the genomic perspective A comprehensive and systematic analysis on the relationship between DNA methylation and gene expression. Therefore, to solve the problems existing in present study, the associations between patterns in the whole genome level of breast cancer DNA methylation and the expression of genes is discussed, the main innovation of the paper are as follows: 1. according to the whole genome of DNA methylation and gene expression of high dimensionality and complexity of relational data, this paper proposes a method to analyze the expression of the relationship between DNA methylation and gene differentiation and analysis based on clustering. This method firstly applies SAM difference analysis method screened the differential expression of CpG gene and differential methylation; then using AP clustering algorithm the difference of methylation of the CpG locus based on similarity clustering to form a plurality of methylation clusters, then for each cluster corresponding to the methylation of gene expression data formed by AP clustering multiple gene expression As clusters, multiple methylation clusters and multiple gene expression clusters is obtained; finally the corresponding cluster methylation data and gene expression data were combined to obtain a variety of association patterns between the two. In the process of clustering, the method by setting the threshold and iterative way to avoid excessive clustering. By mean of cluster as the cluster representative mode to reduce the computational complexity. At the same time, the method can be adjusted according to the difference analysis method and clustering method, has good scalability.2. the study of association pattern of expression of breast cancer DNA gene methylation and whole genome analysis found that association patterns obtained with notable features. First, there are obvious differences between the various types of the diseased samples and normal samples, separated from the basic area. Then according to the differences among samples and normal samples of the distinction between Eight categories in association mode with DNA methylation and gene expression were significantly different between classes, class a similar trend. Finally, each of the categories, with tiny differences in patterns of association between DNA methylation and gene expression, the main difference is that the relevance model within a class with good biological explanation patterns associated with the distribution range of.3. value of the level of experimental analysis proved that the expression of the methylation level and gene. Firstly, the related models are known to exist in breast cancer key pathogenic genes support, provide a basis for the study for the detection of breast cancer and its relationship to the new key basic mode; secondly, to each of the categories of gene sets for biological pathway enrichment analysis showed that the gene set in a number of key pathways in breast cancer are significantly enriched for the development of breast cancer plays an important role in regulation. To sum up, this research From the whole genome level of the relationship between the expression of breast cancer DNA gene methylation and makes a detailed study and analysis, established the pattern of association between breast cancer and gene expression of DNA methylation, but also for the prognosis of breast cancer, diagnosis and treatment provide a method and basis.

【學(xué)位授予單位】：西安電子科技大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R737.9

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